2016
DOI: 10.1002/cmdc.201500551
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Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype‐Selective Ligands

Abstract: A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure affinity relationship data are presented showing that 8-substituted 2,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 receptor over the sigma 1 receptor. Indeed, piperazine analog 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selec… Show more

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Cited by 24 publications
(32 citation statements)
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“…We surmise that norbenzomorphans identified in this and future applications of this powerful HCS assay may be promising leads as therapeutics for neurodegenerative conditions. 22 More generally, we expect this HCS microfluidic technology to be broadly applicable to test small molecules in C. elegans models that capture the subtle cellular phenotypes characteristic of the human disease. The ability to screen whole-animal models at unprecedented speeds and with high resolution will facilitate the identification and translation of promising preclinical candidates.…”
Section: ■ Discussionmentioning
confidence: 99%
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“…We surmise that norbenzomorphans identified in this and future applications of this powerful HCS assay may be promising leads as therapeutics for neurodegenerative conditions. 22 More generally, we expect this HCS microfluidic technology to be broadly applicable to test small molecules in C. elegans models that capture the subtle cellular phenotypes characteristic of the human disease. The ability to screen whole-animal models at unprecedented speeds and with high resolution will facilitate the identification and translation of promising preclinical candidates.…”
Section: ■ Discussionmentioning
confidence: 99%
“…22,23 Briefly, the compounds were dissolved in 100% DMSO prior to the receptor binding assays, which were performed by the Psychoactive Drug Screening Program (PDSP) at Chapel Hill, North Carolina. The assay protocol book can be accessed free of charge at: http://pdspdb.unc.edu/pdspWeb/content/PDSP%20Protocols%20II%202013-03-28.pdf.…”
Section: ■ Methodsmentioning
confidence: 99%
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“…We thus identified a subclass of substituted norbenzomorphans that bind to Sig2R with high affinity (Sahn and Martin ; Sahn et al . ). This is an important discovery because norbenzomorphans have compact molecular scaffolds and may be easily modified for structure‐activity relationship studies.…”
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confidence: 97%